Project description:The present study aimed to study the efficacy and adverse effects of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy in relapsed or refractory multiple myeloma. Patients were divided into three dose groups based on cell therapy concentration. After CAR-T cell therapy for 10 patients with recurrent or refractory multiple myeloma, the patients were monitored and evaluated regularly to observe the efficacy and adverse reactions of CAR-T cell therapy. At a median follow-up of 337 (253-504) days, one patient succumbed 24 days due to rapidly progressing disease. The overall response rate of nine patients was 88.9%, including 77.8% (7/9) with minimal residual disease negative complete remission (CR) and 11.1% (1/9) with partial remission. A total of three patients were maintained in remission state for more than a year and eight were maintained for more than six months. Among the three patients with extramedullary invasion, two extramedullary lesions disappeared and one was stable. The highest copy number of CAR-T cells in seven patients with CR was >1x105 copies/µl gDNA, and the best therapeutic effect can be achieved within 30 (7-30) days after the copy number of CAR-T cells reached 1x105 copies/µl genomic DNA. The median onset time in the nine patients was 43 (22-169) days, and the median progression-free survival was 337 (253-504). Among the 10 patients, nine (90%) had cytokine release syndrome, all of which were below grade II. There were nine (90%) patients with hematological adverse reactions, six (60%) patients with severe anemia, five (50%) patients with grade III and above leukopenia, five (50%) patients with granulocytopenia, four (40%) patients with grade III and above thrombocytopenia, and three (30%) patients with grade III and above pancytopenia. It was concluded that anti-BCMA CAR-T cell therapy is a promising treatment method for relapsed or refractory multiple myeloma and extramedullary invasion, with stable efficacy and controllable adverse effects.

Project description:Multiple myeloma (MM) immune escape resulting from B cell maturation antigen (BCMA) target loss is considered to be a rare event that mediates MM resistance to anti-BCMA chimeric antigen receptor T cell (CAR T) or bispecific T cell engager (TCE) therapies. Emerging clinical data also suggests that downregulation of G protein coupled receptor family C group 5 member D (GPRC5D), another promising target antigen expressed on MM cells, is observed in patients at relapse post anti-GPRC5D CAR T, but the genomic mechanisms that underlie GPRC5D loss has not been described. In order to examine the tumor intrinsic factors that promote MM antigen escape, we performed combined bulk whole genome sequencing and single cell copy number variation analysis on CD138+ cells from bone marrow aspirates of patients before and after relapse from anti-BCMA or -GPRC5D CAR T/ TCE. We describe five cases with distinct biallelic events on TNFRSF17 at MM relapse after CAR T/ TCE. In addition to focal biallelic deletions at the TNFRSF17 locus acquired at relapse, BCMA negative clones can emerge from the selective expansion of subclones with homozygous TNFRSF17 loss that exist prior to any anti-BCMA therapy exposure. Furthermore, we corroborate with functional data to demonstrate that three different non-truncating mutations in the extracellular domain of BCMA negates the efficacies of BCMA directed TCEs and mediate disease relapse in patients. With respect to GPRC5D, we report four cases of MM relapse with biallelic loss of GPRC5D following anti-GPRC5DxCD3ε. Our data support that immunoselection of BCMA negative or mutant clones post anti-BCMA therapies may be more frequent than currently accepted in the field, and that an all or none screening approach for BCMA expression is inadequate to detect pertinent mutations that affect patient response to targeted therapies. We also highlight the importance of developing immunotherapies targeting novel and non-redundant epitopes or antigens in MM

Dataset Information

Beyond BCMA, why GPRC5D could be the right way: treatment strategies with immunotherapy at relapse after anti-BCMA agents.

Publications

Beyond BCMA, why GPRC5D could be the right way: treatment strategies with immunotherapy at relapse after anti-BCMA agents.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets